Leukotriene A.sub.4 (hereinafter, abbreviated as LTA.sub.4) hydrolase, which is one of the epoxide hydrolase, is a metal-containing enzyme which requires zinc in an active center.
LTA.sub.4 hydrolase plays a catalyst-like role on biochemical conversion from LTA.sub.4 into leukotriene B.sub.4 (hereinafter, abbreviated as LTB.sub.4), which is a strong pro-inflammatory substance.
LTB.sub.4 is arachidonic acid metabolitc which is produced in 5-lipoxygenase pathway, biosynthesized in various cells including mast cell, neutrophil, monocyte, macrophage and the like, and plays a role as an important mediator in inflammation. LTB.sub.4 induces chemotaxis, coagulation and degranulation of leukocyte and accumulation of polymorphonuclear leukocyte, and accelerates blood vessel permeability and edema formation. For this reason, it was reported that particularly high level of LTB.sub.4 was detected in lesion parts in inflammatory diseases such as rheumatic diseases (J. Clin. Invest., 66, 116-117 (1980)), psoriasis (Br. J. Pharmacol., 83, 313-317 (1984)), inflammatory bowel diseases (Gastroenterology, 86, 453-460 (1984)) and gout (Lancet, 2, 1122-1124 (1982)) and in sputum in cystic fibrosis (Lancet, 342, 465-469 (1993)).
Therefore, compounds which inhibit LTA.sub.4 hydrolase arc expected to prevent production of LTB.sub.4 and manifest therapeutic effects on inflammatory diseases.
3-Oxiranyl benzoic acid and a derivative thereof were reported to have LTA.sub.4 hydrolase inhibitory activity and be useful as an agent for treating inflammatory diseases such as psoriasis, inflammatory intestinal diseases, arthritis and gout (JP-A 2-134375).
In addition, (+)-1-(3S, 4R)-3-(4-phenylbenzyl)-4-hydroxychroman-7-yl!cyclopentanecarboxylic acid was reported to have LTA.sub.4 hydrolase inhibitory activity and inhibit sideration of arthritis in a collagen-induced arthritis model (J. Med. Chem., 37, 3197-3199 (1994)).
On the other hand, the structural features of the present invention is in amino acid having a sulfur or oxygen atom in which the sulfur or oxygen atom is bonded with (N,N-dialkylaminophenyl)alkyl, and an amino group is bonded to a sulfur-containing acyl group. From a viewpoint of the chemical structure, the prior art will be described below.
Compounds in which a phenyl group is introduced on a side chain of a sulfur-containing amino acid derivative was reported to be useful as a therapeutic agent for rheumatoid diseases and a hypotensive agent (JP-A 61-165362), because the compounds have rheumatoid factor's inactivating activity and angiotensin converting enzyme inhibitory activity, and also have endopeptidase 24.11 inhibitory activity (J. Med. Chem., 37, 2461-2476 (1994). However, a phenyl ring in amino acid side chain in the compounds described in these reports is not substituted and, thus, there is no description on compounds in which a substituent is introduced in a phenyl ring.
As described above, although various studies were done on sulfur-containing amino acid derivatives having a non-substituted phenyl ring on a side chain, no study has been done yet on sulfur-containing and oxygen-containing amino acid derivatives in which an N,N-dialkylamino group is introduced on its phenyl ring. Thus, a study regarding synthesis of the above compounds and a study regarding their pharmacological activities, particularly, activities on LTA.sub.4 hydrolase were very interesting themes.